The Consortium of Food Allergy Research (CoFAR) has begun a series of studies intended to address both the etiology of and potential cure for food allergy. One of the planned clinical trials will evaluate the effectiveness of gradually administering peanut allergen by mouth (oral immunotherapy or OIT) on protecting patients from allergic reactions and ultimately curing them of their allergy. Patients with peanut allergy have an immune response to peanut allergens that results in the production of immunoglobulin E (IgE). IgE is bound by receptors on immune cells, such as basophils, and can lead to the release of histamine and other substances when it comes into contact with peanut allergen. It has been shown that OIT can induce the production of allergen-specific immunoglobulin G (IgG) antibody. This IgG antibody, in contrast to IgE antibody, may be protective, though the mechanism of its protection is not well understood. In addition, by a poorly understood process termed, `clinical desensitization', OIT appears to protect people from severe reactions by making them less sensitive to additional accidental exposures. Previous studies have suggested that IgG inhibits IgE by interacting with inhibitory IgG receptors on basophils, although other studies have suggested instead that IgG may simply prevent allergen from binding to the IgE. To date, no studies have been designed in such a way as to allow evaluation of these alternative mechanisms on an individual basis in the context of a clinical trial. We hypothesize, that OIT induces inhibitory immune changes that prevent the IgE-induced release of histamine from basophils. We would like to test our hypothesis by focusing on three aims: First, we would like to establish how frequently inhibitory IgG is induced by OIT. Second, we would like to determine whether IgG is primarily blocking allergen from IgE or interacting with inhibitory receptors on basophils. Third, we would like to understand how gradual introduction and rapid (hours to days) escalation of allergen to a dose that would previously have caused a reaction (clinical desensitization) affects patients'basophils. In order to do this, we intend to take advantage of our cumulative experience in measuring basophil activation by flow cytometry, and begin for the first time to directly examine intracellular signals that result from the stimulation of the cells via the IgE and IgG receptors. We believe we have a unique opportunity to conduct a small, self-contained research project that complements an already funded large prospective clinical study of oral immunotherapy for food allergy. This project has the potential both to give new and unique insight into the mechanisms of oral immunotherapy and to establish innovative methods for the assessment of basophil activation by direct measurement of intracellular signaling molecules. PUBLIC HEALTH RELEVANCE Food allergy affects 6-8% of children and 2-4% of adults and is increasing. Food allergy accounts for approximately 30,000 episodes of anaphylaxis and 100-200 deaths. This proposal is to study how allergen immunotherapy can protect people so that ultimately it can be more effective.